The goal of this Phase II SBIR project is to develop a clinically useful potentiator of the most widely used antifungal drugs, azoles. The major shortcoming of azole drugs is that they do not kill fungi but merely inhibit their growth. In fact, for the most medically important fungal pathogen, Candida albicans, this growth inhibition is only partial. The survival of the pathogen in the presence of the drug is the likely cause of the recurrence of fungal infections and emergence of azole resistance. Our Phase I studies identified two compounds in whose presence azoles become strongly fungicidal. These compounds show no antifungal activity on their own and no toxicity to human cells in culture. Structural derivatives of these two leads, displaying improved activity and pharmacological properties, will be obtained through intensive synthetic efforts. The biological activity of these derivatives will be thoroughly characterized in vitro. Their ability to improve antifungal activity of fluconazole will be tested in a murine model of systemic candidiasis. Finally, the molecular mechanism of action of the potentiators will be investigated in biochemical and genetic experiments. It is expected that the compounds developed in this project will significantly improve the improve the effectiveness of antifungal therapy. PROPOSED COMMERCIAL APPLICATION: The commercial product envisioned is a fungicidal combination of fluconazole with an adjuvant that potentiates antifungal activity. Such a product would have a major impact on the therapeutic and prophylactic treatment options for systemic Candida infections